ABSTRACT The hippocampus contains dense patterns of synaptic connectivity that allows for sophisticated information processing but makes this network vulnerable to instability. In recent years, homeostatic forms of synaptic plasticity (HSP) have been recognized to play a central role in buffering destabilizing levels of activity in neural circuits. Perhaps the most widely studied form of HSP is ?synaptic scaling,? a process whereby synapses are enhanced or depressed multiplicatively in response to chronic changes in neural firing rate. Although synaptic scaling has been extensively studied and linked to a number of neurological and neuropsychiatric disorders, the slow time-course over which scaling occurs has remained a perplexing feature of this adaptive form of plasticity. Reasoning that the temporal dynamics of scaling might be dependent on the activity-dependent history of the circuit, my preliminary experiments have examined how prior experience with scaling shapes the magnitude and time-course of adaptation to future activity challenges. Surprisingly, I have found hippocampal neuron networks respond to destabilizing levels of activity differently depending on their activity-dependent history, suggesting a novel form of metaplasticity that potently regulates the induction of synaptic scaling. The long-term goal of this research is to understand the contribution of activity-dependent epigenetic changes to the metaplastic regulation of HSP in hippocampal neurons. The central hypothesis guiding this proposal is that synaptic scaling induces lasting epigenetic changes which subsequently alters the intrinsic and/or synaptic properties of neurons, fundamentally altering the ability to shift synaptic weights in response to additional activity manipulations. This work will use cutting edge electrophysiological, imaging, and sequencing methods to determine the functional significance of transcription-level changes to the metaplastic regulation of synaptic scaling and how this impacts the stability of the overall network. By characterizing this novel aspect of synaptic scaling, this project will provide insights into fundamental aspects of homeostatic regulation in neural circuits.